Pharmaceutical compositions and methods for anesthesiological applications

ABSTRACT

Pharmaceutical compositions and methods for inducing conscious sedation using such compositions are described, the compositions comprising a benzodiazepine-based compound, a NMDA antagonist, and optionally a β-blocker, antiemetic, an NSAID, and/or an antihistamine medication. Methods for fabricating the compositions and using them for anesthesiological applications are also described.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part application claiming the benefit ofpriority under 35 U.S.C. § 120 to U.S. application Ser. No. 15/903,529,filed Feb. 23, 2018, now pending, which is a continuation-in-part ofSer. No. 15/184,768, filed Jun. 16, 2016, now issued as U.S. Pat. No.9,918,993, which claims the benefit of priority under 35 U.S.C. § 119(e)of U.S. Provisional App. No. 62/182,130, filed Jun. 19, 2015, the entirecontent of each of which is incorporated herein by reference. Thisapplication is also a continuation-in-part claiming the benefit ofpriority under 35 U.S.C. § 120 to U.S. application Ser. No. 15/903,615,filed Feb. 23, 2018, now pending, which is a continuation-in-part ofSer. No. 15/184,768, filed Jun. 16, 2016, now issued as U.S. Pat. No.9,918,993, which claims the benefit of priority under 35 U.S.C. § 119(e)of U.S. Provisional App. No. 62/182,130, filed Jun. 19, 2015, the entirecontent of each of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to the field of pharmacology andmore specifically to compositions having anesthetic properties that areuseful in various kinds of surgery, e.g., ophthalmic surgery, and tomethods of preparing and using such compositions.

BACKGROUND

The present disclosure relates to solid or liquid pharmaceuticalformulations comprising combinations of active agents such asanesthetics, anti-emetics, anti-hypertensives, anti-anxiety medicationsand/or analgesics, and methods for using the same for providinganesthesia by administering such compositions rectal administration,nasal administration (including via a nasal spray), oral sprayadministration, transdermal administration, and transmucosaladministration including that utilizing a transmucosal gel. Theformulations may also include slow release reversal agents that wouldcounteract the initial anesthesia effect.

It is necessary in many cases to use local anesthesia, particularly viasuch routes of administration in the course of various surgicalprocedures, e.g., ophthalmic surgeries or urological interventions. Forinstance, when local anesthesia is employed during or prior tointraocular operations, the occurrences of pain, anxiety, peri-operativestress, nausea, agitation, vomiting and the like are less frequent,which will typically have a very beneficial effect on the surgicalexperience and reducing the number of intraocular complications such asbleeding, secretions, cardiac and/or pulmonary complications, etc. Theseverity of those complications when they do occur will also be lesspronounced when local anesthesia is used.

Traditionally, an intravenous route is used to administer suchmedications. Alternatives to intravenous methods and therapies have beensuggested and previously used for the treatment. In particular, oraladministration of benzodiazepines, opioid analgesics, propofol, ketamineor etomidate utilizing the MAC procedure (monitored anesthesia care) hasbeen suggested and tried, but no more than minimal to moderateimprovement has been achieved by such methods. Therefore, there remainsa need for better treatments of these disorders.

This patent specification discloses such pharmaceutical compositionssuitable for anesthesiological applications that can achieve positivepatient outcomes while being free of drawbacks and deficiencies ofexisting methods and formulations. Methods of fabricating andadministering the same are also discussed.

SUMMARY

According to one embodiment of the invention, there are providedpharmaceutical compositions. The compositions include a therapeuticallyeffective quantity of at least one first pharmaceutically activecompound comprising benzodiazepine moiety or pharmaceutically acceptablesalts, hydrates, solvates or N-oxides thereof, a therapeuticallyeffective quantity of at least one second pharmaceutically activecompound that is an NMDA antagonist or pharmaceutically acceptablesalts, hydrates, solvates or N-oxides thereof, and at least onepharmaceutically acceptable excipient or carrier therefor.

According to another embodiment of the invention, the pharmaceuticalcompositions described above may further include a therapeuticallyeffective quantity of at least one third pharmaceutically activecompound that is a β-blocker, an NSAID, or an antiemetic medicament, ora combination thereof, or pharmaceutically acceptable salts, hydrates,solvates or N-oxides thereof.

According to further embodiments of the invention, in the pharmaceuticalcompositions described above, the first pharmaceutically active compoundmay be any of midazolam, diazepam, lorazepam, flunitrazepam, alprazolam,chlordiazepoxide, clonazepam or clorazepate, the second pharmaceuticallyactive compound may be any of ketamine, dextrorphan, etomidate,methadone, memantine, amantadine or dextromethorphan and the thirdpharmaceutically active compound may be (if a β-blocker) any ofmetoprolol, propranolol, acebutolol, nadolol, atenolol, betaxolol,esmolol, bisoprolol fumarate, carvedilol, nebivolol, penbutolol,timolol, or sotalol or (if an antiemetic) ondansentron, dolasetron,granisetron, palonosetron, promethazine, imenhydrinate, or meclizine.

According to yet another embodiment of the invention, there are providedfurther pharmaceutical compositions such as any described above, whereinthe compositions are formulated as an item suitable for rectaladministration, nasal administration (including via a nasal spray), oralspray administration, transdermal administration, and transmucosaladministration including that utilizing a transmucosal gel.

According to other embodiments, there are provided specific compoundsfor making the compositions described above, for example, midazolam,ketamine and ondansetron, as well as methods for using above-mentionedcomposition(s) for the purposes of local anesthesia in variousapplications, such as ophthalmic surgery.

According to further embodiments of the invention, the above-mentionedmethods of using the composition(s) include administering to a patientin need thereof (i.e., those patients who require conscious sedation orpre-sedation) a pharmaceutical composition described herein as the firststep of the medical or surgical procedure, the procedure being anophthalmic surgery (e.g., a cataract, glaucoma, corneal, eyelid surgery,or retinal surgery), a dental procedure (e.g., a tooth extraction, anoral surgery, or a root canal surgery), an outpatient medical procedure(e.g., medical imaging procedure, biopsy, bone marrow harvesting,colonoscopy, or endoscopy), a urological procedure (e.g., vasectomy), alaparoscopic procedure, obstetric and gynecological procedures, agastrointestinal procedure, an otolaryngological procedure, a cosmeticsurgery procedure, a dermatological procedure, a podiatric procedure, anorthopedic procedure, an emergency medical treatment, a psychiatrictreatment, or a veterinarian procedure.

DETAILED DESCRIPTION A. Terms and Definitions

Unless specific definitions are provided, the nomenclatures utilized inconnection with, and the laboratory procedures and techniques ofanalytical chemistry, synthetic organic and inorganic chemistrydescribed herein, are those known in the art. Standard chemical symbolsare used interchangeably with the full names represented by suchsymbols. Thus, for example, the terms “hydrogen” and “H” are understoodto have identical meaning. Standard techniques may be used for chemicalsyntheses, chemical analyses, formulating compositions and testing them.The foregoing techniques and procedures can be generally performedaccording to conventional methods well known in the art.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise. The section headings used herein are for organizationalpurposes only and are not to be construed as limiting the subject matterdescribed.

As used herein, “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“includes,” and “included,” is not limiting.

“About” as used herein means that a number referred to as “about”comprises the recited number plus or minus 1-10% of that recited number.For example, “about” 100 degrees can mean 95-105 degrees or as few as99-101 degrees depending on the context. Whenever it appears herein, anumerical range such as “1 to 20” refers to each integer in the givenrange; i.e., meaning only 1, only 2, only 3, etc., up to and includingonly 20.

The term “pharmaceutical composition” is defined as a chemical orbiological compound or substance, or a mixture or combination of two ormore such compounds or substances, intended for use in the medicaldiagnosis, cure, treatment, or prevention of disease or pathology.

The terms “anesthetic,” “anesthesia,” “anesthesiology” and the likerefer herein to substances, compounds, processes or procedures thatinduce insensitivity to pain such as a temporary loss of sensation.

The term “conscious sedation” that for the purposes of this applicationmay be used interchangeably with the terms “procedural sedation” and“analgesia” is used herein to refer to an induced state of sedationcharacterized by a minimally depressed consciousness such that thepatient is able to continuously and independently maintain a patentairway, retain protective reflexes, and remain responsive to verbal cuesand/or tactile or physical stimulation.

Conscious sedation is typically performed to decrease the level ofanxiety in a patient and to elicit an improved degree of cooperationfrom the patient. Conscious sedation, therefore, refers to a conditionthat is medically different and distinct from deep sedation which is thenext level of sedation defined as depression of consciousness when thepatient's ability to independently maintain ventilatory function may beimpaired and he or she cannot be easily aroused; however, the patientwill still purposefully respond to repeated or painful stimulation.

Conscious sedation is also clearly distinguishable for the purposes ofthe present application from the lower level of sedation (i.e., minimalsedation when the patient is able to maintain a normal response toverbal stimuli) as well as the highest level of sedation (i.e., generalanesthesia when there is no response from the patient even with painfulstimulus).

The term “pre-sedation” is defined for the purposes of this applicationas conscious sedation that is induced some time before the procedures,e.g, between 5 minutes and 1 hour prior.

The terms “solvate” and “hydrate” are used herein to indicate that acompound or substance is physically or chemically associated with asolvent for “solvates” such as water (for “hydrates”).

The term “NMDA antagonist” is defined as a compound that inhibits(“antagonizes”) the action of the N-methyl-D-aspartate receptors and isinclusive of both competitive and non-competitive antagonists, glycineantagonists and uncompetitive channel blockers, as these terms areunderstood by those having ordinary skill in the art.

The term “β-blocker” refers to a compound of any kind that can preventor reduce the stimulation of the adrenergic receptors responsible forincreased cardiac action.

The term “antiemetic” is defined as a drug or medicament that treats,reduces, and/or prevents nausea and/or vomiting.

The term “non-steroid anti-inflammatory drug” or “NSAID” refers to aclass of compounds that are free of any steroid moieties yet are capableof providing analgesic, antipyretic and/or anti-inflammatory effects.

The term “antihistamine medicament” refers to any compound that iscapable of inhibiting or counteracting the physiological effects ofhistamine.

The term “polyglycol” is defined as a polymer or oligomer containingseveral ether-glycol linkages that yields one or more glycols when theselinkages are cleaved, e.g., by hydrolysis.

The term “carrier” refers to a substance that serves as a vehicle forimproving the efficiency of delivery and the effectiveness of apharmaceutical composition.

The term “excipient” refers to a pharmacologically inactive substancethat is formulated in combination with the pharmacologically activeingredient of pharmaceutical composition and is inclusive of bulkingagents, fillers, diluents and products used for facilitating drugabsorption or solubility or for other pharmacokinetic considerations.

The term “therapeutically effective amount” is defined as the amount ofa compound or pharmaceutical composition that will elicit the biologicalor medical response of a tissue, system, animal or human that is beingsought by the researcher, medical doctor or other clinician.

The term “pharmaceutically acceptable” when used in reference to acarrier, whether a diluent or excipient, refers to a substance that iscompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The terms “administration of a composition” or “administering acomposition” is defined to include an act of providing a compound of theinvention or pharmaceutical composition to the subject in need oftreatment.

The term “rectal administration” is broadly defined as a route ofadministration where a medication is inserted directly to the rectum ofa patient for absorption by the rectum's blood vessels and flow into thebody's circulatory system.

The term “nasal administration” (e.g., via a spray) is broadly definedas a route of administration in which a medication is insufflateddirectly through the patient's nasal cavity; e.g., a liquid medicinethat is atomized into a fine spray and inhaled through the nose.

The term “oral spray administration” is defined as a route ofadministration whereby a medication is delivered via a spray through thepatient's mouth (e.g., a liquid medicine that is atomized into a finespray and inhaled through the mouth).

The term “transdermal administration” is defined as a route ofadministration whereby a medication is delivered through the skin of thepatient for distribution throughout the patient's entire body.

The term “transmucosal administration” is defined as a route ofadministration whereby a medication is delivered through the mucousmembrane, e.g., via inhalation, nasally, sublingually, buccally,vaginally, rectally, or ocularly.

B. Embodiments of the Invention

According to embodiments of the present invention, there are providedpharmaceutical compositions for anesthetic purposes. The compositionscomprise, consist of or consist essentially of, a combination oftherapeutically effective quantities of at least one firstpharmaceutically active compound and at least one secondpharmaceutically active compound. In some further embodiments, thecompositions optionally comprise, in addition to the above-mentionedfirst and second pharmaceutically active compounds, at least one thirdpharmaceutically active compound.

The first pharmaceutically active compound that is used in suchcomposition comprises benzodiazepine moiety or pharmaceuticallyacceptable salts, hydrates, solvates or N-oxides thereof. Those havingordinary skill in the art will know that benzodiazepine moiety is astructure where a benzene ring is condensed with diazepine ring, aseven-member heterocycle with two nitrogen atoms which for the purposesof this specification may be in any positions of the ring (e.g.,1,2-diazepine, 1,3-diazepine or 1,4-diazepine). An example of a compoundhaving benzodiazepine moiety with 1,4-diazepine structure is shownbelow:

One particular first pharmaceutically active compound comprisingbenzodiazepine moiety that can be used in pharmaceutical compositionsdescribed and claimed herein is midazolam. Other specific, non-limitingexamples of first pharmaceutically active compounds comprisingbenzodiazepine moiety that can be used include diazepam, lorazepam,flunitrazepam, alprazolam, chlordiazepoxide, clonazepam, clobazam,bromazepam, prazepam, oxazepam and clorazepate. Each of these is alsoknown under one or several trade names as shown in Table 1, which alsodiscloses chemical names of such compounds. Those having ordinary skillin the art can select alternative suitable benzodiazepine-based compoundfor using in the compositions, if so desired.

TABLE 1 Examples of Benzodiazepine-Based Compounds That Can Be Used inCompositions Compound Chemical Name (IUPAC) Trade Name(s) Midazolam8-chloro-6-(2-fluorophenyl)-1-methyl-4H- VERSED ®, DORMICUM ®,imidazo[1,5-a][1,4]benzodiazepine HYPNOVEL ® Diazepam7-chloro-1-methyl-5-phenyl-3H-1,4- VALIUM ®, DIASTAT ®benzodiazepin-2-one Lorazepam 7-chloro-5-(2-chlorophenyl)-3-hydroxy-TEMESTA ®, ATIVAN ®, 1,3-dihydro-2H-1,4-benzodiazepin-2-one ORFIDAL ®Flunitrazepam 5-(2-fluorophenyl)-1-methyl-7-nitro-1H- ROHYPNOL ®,NARCOZEP ® benzo[e][1,4]diazepin-2(3H)-one and many others Alprazolam8-chloro-1-methyl-6-phenyl-4H- XANAX ®[1,2,4]triazolo[4,3-a][1,4]benzodiazepine Chlordiazepoxide7-chloro-2-methylamino-5-phenyl-3H-1,4- LIBRIUM ® benzodiazepine-4-oxideClonazepam 5-(2-chlorophenyl)-7-nitro-2,3-dihydro- KLONOPIN ®,RIVOTRIL ® and 1,4-benzodiazepin-2-one many others Clorazepate7-chloro-2,3-dihydro-2-oxo-5-phenyl- TRANXENE ®1H-1,4-benzodiazepine-3-carboxylic acid Bromazepam7-bromo-5-(pyridin-2-yl)-1H- LEXOTAN ®, LEXOTANIL ®benzo[e][1,4]diazepin-2(3H)-one and many others Oxazepam7-chloro-3-hydroxy-5-phenyl-2,3-dihydro- ALEPAM ®, SERAX ® and many1H-1,4-benzodiazepine-2-one others Clobazam7-chloro-1-methyl-5-phenyl-1,5- URBANOL ®, FRISIUM ®,benzodiazepine-2,4(3H)-dione ONFI ® Prazepam7-chloro-1-(cyclopropylmethyl)-5-phenyl- LYSANXIA ®, CENTRAX ® and1,3-dihydro-2H-1,4-benzodiazepin-2-one many others

The therapeutically effective quantity of the benzodiazepine-basedcompound(s) in the entire pharmaceutical composition can be betweenabout 0.01 mass % and about 5.0 mass % of the composition. In someembodiments, the therapeutic effective amount of thebenzodiazepine-based compound(s) can be between about 1.0 mass % andabout 3.0 mass %, for example, about 2.5 mass % of the composition.

In some applications a patient may be extra sensitive to benzodiazepines(e.g., may become excessively drowsy). For such patients, there areprovided additional embodiments in which benzodiazepine(s)-containingpharmaceutical compositions described above, would additionally includea quantity of a receptor antagonist to benzodiazepines. Such a receptorantagonist would begin counteracting the effect of benzodiazepine afterthe surgical procedure is complete, in essence providing a slow releasefeature. A non-limiting example of this antagonist is flumazenil alsoknown under trade names such as ANEXATE®, ROMAZICON® and others. The useof antagonists is also envisioned as a routine practice (i.e., not justfor sensitive patients), for example, in situations when larger thantypical or usual dosage of benzodiazepines is medically indicated, orrecommended, or necessary. In some further applications,benzodiazepine-based compounds may be used in combination withnon-benzodiazepine based sedatives such as eszopiclone, ramelteon,zolpidem, or zaleplon.

The second pharmaceutically active compound that is used in suchcomposition is an NMDA antagonist, as this term is defined hereinabove,or pharmaceutically acceptable salts, hydrates, solvates or N-oxidesthereof. One particular second pharmaceutically active compound that canbe used in pharmaceutical compositions described and claimed herein isketamine. Other specific, non-limiting examples of NMDA antagonists thatcan be used include dextrorphan, etomidate, methadone, memantine,amantadine and dextromethorphan. Each of these is also known under oneor several trade names as shown in Table 2, which also discloseschemical names of such compounds. Those having ordinary skill in the artcan select alternative suitable NMDA antagonists for using in thecompositions, if so desired.

TABLE 2 Examples of NMDA Antagonists That Can Be Used in CompositionsCompound Chemical Name (IUPAC) Trade Name(s) Ketamine2-(2-chlorophenyl)-2- KETANEST ®, (methylamino)cyclohexanone KETASET ®,KETALAR ® (HCL salt) Dextrorphan 17-methyl-9a,13a,14a-morphinan-3-olNone Etomidate Ethyl-3-[(1R)-1-phenylethyl]imidazole-5- AMIDATE ®,carboxylate HYPNOMIDATE ® Methadone6-(dimethylamino)-4,4-diphenylheptan-3-one DOLOPHINE ®, AMIDONE ® andothers Memantine 3,5-dimethyladamantan-1-amine AKATINOL ®, NAMENDA ® andothers Amantadine Adamantan-1-amine SYMMETREL ® Dextromethorphan(4bS,8aR,9S)-3-methoxy-11-methyl-6,7,8,8a,9,10- ROBITUSSIN ®,hexahydro-5H-9,4b-(epiminoethano)phenanthrene DELSYM ® and others

The therapeutically effective quantity of the NMDA antagonist(s) in theentire pharmaceutical composition can be between about 1.0 mass % andabout 20.0 mass % of the composition. In some embodiments, thetherapeutically effective amount of the NMDA antagonist(s) can bebetween about 4.0 mass % and about 16.0 mass %, for example, about 5.0mass % of the composition. Accordingly, the combined quantities of boththe benzodiazepine-based compound(s) and the NMDA antagonist(s), takentogether, in the entire pharmaceutical composition can be between about1.2 mass % and about 15.0 mass % of the composition, such as betweenabout 3.0 mass % and about 12.0 mass %, for example, about 10.0 mass %of the composition.

As mentioned above, the compositions may further optionally comprise atleast one third pharmaceutically active compound. In such embodiments,the third pharmaceutically active compound is a β-blocker, as this termis defined hereinabove, or pharmaceutically acceptable salts, hydrates,solvates or N-oxides thereof, or alternatively α-2-adrenergic agonistor, as another alternative, a pain reliever. In addition to, or insteadof, β-blockers, the third pharmaceutically active compound may alsocomprise an antiemetic medicament, as this term is defined hereinabove,or pharmaceutically acceptable salts, hydrates, solvates or N-oxidesthereof.

In yet another aspect, the third pharmaceutically active compound mayinclude one or several non-steroid anti-inflammatory drug(s) (NSAID's),as this term is defined hereinabove. NSAID(s) may be so used in additionto, or instead of, β-blocker(s), and/or antiemetic(s). In a furtheraspect, the third pharmaceutically active compound may also comprise anantihistamine medicament, as this term is defined hereinabove,non-limiting examples of specific antihistamine medicaments that can beso used being any of hydroxyzine pamoate, hydroxyzine hydrochloride,diphenhydramine hydrochloride, meclizine, chlorpheniramine, clemastine,promethazine, or prochlorperazine, or any combination thereof. Again,antihistamine medicaments may be used in addition to, or instead of, anyabove-mentioned compound that may be used as the third pharmaceuticallyactive compound.

The therapeutically effective quantity of the third pharmaceuticallyactive compound(s) in the entire pharmaceutical composition can bebetween about 0.1 mass % and about 5.0 mass % of the composition. Insome embodiments, the therapeutic effective amount of the thirdpharmaceutically active compound(s) can be between about 1.0 mass % andabout 4.0 mass %, for example, about 2.5 mass % of the composition.

One particular β-blocker that can be used as the third pharmaceuticallyactive compound in pharmaceutical compositions described and claimedherein is metoprolol. Other specific, non-limiting examples ofβ-blockers or α-2-adrenergic agonists or pain relievers that can be usedinclude, propranolol, acebutolol, nadolol, atenolol, betaxolol, esmolol,bisoprolol fumarate, carvedilol, nebivolol, penbutolol, timolol,sotalol, dexmedetomidine hydrochloride, clonidine, and acetaminophen.Each of these is also known under one or several trade names as shown inTable 3, which also discloses chemical names of such compounds. Thosehaving ordinary skill in the art can select alternative suitableβ-blockers for using in the compositions, if so desired.

TABLE 3 Examples of β-Blockers That Can Be Used in Compositions CompoundChemical Name (IUPAC) Trade Name(s) Metoprolol1-(isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol LOPRESSOR ®,TOPROL ® Propranolol 1-(1-methylethylamino)-3-(1-naphthyloxy)propan-2-olCIPLA ®, INDERAL ®, and many others AcebutololN-{3-acetyl-4-[2-hydroxy-3-(propan-2-ylamino) SECTRAL ®,propoxy]phenyl}butanamide PRENT ® Nadolol5-{[3-(tert-butylamino)-2-hydroxypropyl]oxy}-1,2,3,4- CORGARD ®tetrahydronaphthalene-2,3-diol Atenolol2-{4-[2-hydroxy-3-(propan-2-ylamino)propoxy] TENORMIN ® phenyl}acetamideBetaxolol 1-{4-[2-(cyclopropylmethoxy)ethyl]-phenoxy}-3- KERLONE ®,(isopropylamino)propan-2-ol BETOPTIC ®, and others Esmolol3-{4-[2-hydroxy-3-(propan-2-ylamino)propoxy] BREVIBLOC ®phenyl}propanoate Bisoprolol1-[4-[[2-(1-methylethoxy)ethoxy]methyl]phenoxy]-3[(1- ZEBETA ® fumaratemethylethyl)amino]-2-propanol-2-butenedioate Carvedilol3-(9H-carbazol-4-yloxy)-2-hydroxypropyl-2-(2- COREG ®,methoxyphenoxy)ethylamine CARVIL ® and many others Nebivolol2,2′-azanediylbis(1-(6-fluorochroman-2-yl)ethanol) NEBILET ®, BYSTOLIC ®Penbutolol 1-(tert-butylamino)-3-(2-cyclopentylphenoxy)propan-2-olLEVATOL ®, LEVATOLOL ®, and many others Timolol1-(tert-butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3- TIMOPTIC ®,yl)oxy]propan-2-ol BETIMOL ® and many others SotalolN-{4-[1-hydroxy-2-(propan-2-ylamino)ethyl]phenyl} BETAPACE ® andmethanesulfonamide others

One particular antiemetic that can be used as the third pharmaceuticallyactive compound in pharmaceutical compositions described and claimedherein is ondansetron. Other specific, non-limiting examples ofantiemetics that can be used include dolasetron, granisetron,palonosetron, promethazine, imenhydrinate, and meclizine. Each of theseis also known under one or several trade names as shown in Table 4,which also discloses chemical names of such compounds. Those havingordinary skill in the art can select alternative suitable antiemeticsfor using in the compositions, if so desired.

TABLE 4 Examples of Antiemetics That Can Be Used in CompositionsCompound Chemical Name (IUPAC) Trade Name(s) Ondansetron(RS)-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-2,3- ZOFRAN ®,dihydro-1H-carbazol-4(9H)-one ONDISOLV ® Dolasetron(2α,6α,8α,9aβ)-octahydro-3-oxo-2,6-methano-2H-quinolizin- ANZEMET ®8-yl-1H-indole-3-carboxylate monomethanesulfonate, monohydrateGranisetron 1-methyl-N-((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-KYTRIL ® yl)-1H-indazole-3-carboxamide Palonosetron(3aS)-2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6- ALOXI ®hexahydro-1H-benz[de]isoquinolin-1-one Promethazine(RS)-N,N-dimethyl-1-(10H-phenothiazin-10-yl)propan-2- PHENERGAN ® amineDimenhydrinate 2-benzhydryloxy-N,N-dimethylethanamine; 8-chloro-1,3-DRAMAMINE ®, dimethyl-7H-purine-2,6-dione GRAVOL ®, VOMEX ®, many othersMeclizine (RS)-1-[(4-chlorophenyl)(phenyl)methyl]-4-(3- BONINE ®,methylbenzyl)piperazine BONAMINE ®, ANTIVERT ®, and many others

Therefore, the combined quantities of all the pharmaceutically activecompounds (i.e., the benzodiazepine-based compound(s), the NMDAantagonist(s), the β-blocker(s)), and/or the antiemetic(s) takentogether, in the entire pharmaceutical composition can be between about1.3 mass % and about 20.0 mass % of the composition, such as betweenabout 3.0 mass % and about 12.0 mass %, for example, about 10.0 mass %of the composition. Those having ordinary skill in the art willdetermine the most appropriate quantities of each the pharmaceuticallyactive compound that are within the above-mentioned ranges and that aremost suitable for a particular patient. As a guideline only, thefollowing mass ratios between the pharmaceutically active compounds maybe used (Table 5) for compositions where the benzodiazepine-basedcompound is midazolam, the NMDA antagonist is ketamine hydrochloride andthe β-blocker is propanolol hydrochloride:

TABLE 5 Exemplary Mass Ratios Between Midazolam, Ketamine Hydrochlorideand Propanolol Hydrochloride in the Compositions Ketamine PropanololRatios Midazolam Hydrochloride Hydrochloride Between about 1 2 1 andabout 1 10 1 Such as between about 1 4 1 and about 1 6 1 For example 1 51

In one specific embodiment, which is exemplary and non-limiting, for thecomposition having midozalam as the first pharmaceutically activecompound, ketamine as the second pharmaceutically active compound andondansentron as the third pharmaceutically active compound, the massmidazolam:ketamine:odansentron ratio may be about 3:25:2.

The pharmaceutical compositions described herein may contain not onlypharmaceutically active components but also, in some embodiments, mayfurther comprise one or several inactive, neutral compounds which can bepharmaceutically acceptable excipient(s) or carrier(s), including, butnot limited to, binder(s), antioxidant(s), adjuvant(s), synergist(s)and/or preservative(s). The mass concentration of such inactivecompounds can be between about 80 mass % and about 99 mass % of theentire pharmaceutical composition, such as between about 85 mass % andabout 95 mass %, e.g., about 90 mass %.

Some embodiments of the invention are directed to pharmaceuticalformulations that are formulated as suitable for rectal administration,nasal administration (including via a nasal spray), oral sprayadministration, transdermal administration, and transmucosaladministration including that utilizing a transmucosal gel. In certainembodiments, these compositions may optionally comprise binder(s) and/orexcipient(s). They can be prepared by first mixing the pharmaceuticallyactive compounds described above with suitable binder(s) and/orexcipient(s) followed by molding or compressing, if applicable.

Typical binder(s) that can be used for fabricating the formulationsmentioned above include, without limitation, polyglycols as definedabove, such as, e.g., polyethylene glycols (PEGs), polyethylene oxides(POE), methoxypolyethylene glycols, polypropylene glycols, polybutyleneglycols or derivatives thereof having a molecular weight that issufficient to provide the necessary hardness and time for dissolution ofthe troche; for example, the acceptable molecular weight can be withinthe range of between about 1,000 Daltons and about 8,000 Daltons. Insome embodiments PEG-1450 or PEG-400 can be used. Non-limiting examplesof some specific polyglycol derivatives that can be used are:

(a) PEG-laureates and dilaureates (e.g., PEG-10-, PEG-12-, PEG-20-,PEG-32-laurates, PEG-20- and PEG-32-dilaurates, PEG-20-glyceryl-,PEG-30-glyceryl- and PEG-40-glyceryl-laurates, PEG-80-sorbitan laurate);

(b) PEG-oleates, dioleates and trioleates (e.g., PEG-12-, PEG-15-,PEG-20-, PEG-32, PEG-200- and PEG-400-oleates, PEG-20- andPEG-32-dioleates, PEG-20-trioleate, PEG-25-glyceryl trioleate,PEG-20-glyceryl- and PEG-30-glyceryl-oleates, PEG-40-sorbitan oleate);

(c) PEG-stearates and distearates (e.g., PEG-15-, PEG-40-,PEG-100-stearates, PEG-32-distearate and PEG-20-glyceryl stearate)

(d) castor, palm kernel, corn and soya oil derivatives of PEG (e.g.,PEG-35-, PEG-40- and PEG-60-castor oils, PEG-40-, PEG-50- andPEG-60-hydrogenated castor oils, PEG-40-palm kernel oil, PEG-60-cornoil, PEG-30-soya sterol);

(e) other PEG derivatives (e.g., PEG-24- and PEG-30-cholesterol,PEG-25-phytosterol, PEG-6- and PEG-8-caprate/caprylate glycerides,tocopheryl PEG-100 succinate, PEG-15-100 octylphenol products andPEG-10-100 nonylphenol products);

(f) other products such as polyglyceryl-10-laurate, POE-9- andPOE-23-lauryl ethers, POE-10- and POE-20-oleyl ethers, POE-20-stearylether, polysorbates-20 and 80, polyglyceryl-10-oleate, Tween 40, Tween60, sucrose monostearate, monolaurate and monopalmitate and variousproducts of Poloxamer series.

Typical excipient(s) that can be used for fabricating the compositionsmentioned above include, without limitation, gelatin, sodium saccharin,stevioside, peppermint oil, cherry flavor, lemon oil, raspberry flavor,or any natural or artificial fruit, vegetable, flower, beverage or candyflavor.

As stated above, the compositions may optionally further comprise one orseveral antioxidant(s). If antioxidant(s) are used, non-limitingexamples of those that can be used include α-tocopherol acetate, acetonesodium bisulfite, acetylcysteine, ascorbic acid, ascorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, cysteine, cysteinehydrochloride, tocopherol natural, tocopherol synthetic, dithiothreitol,monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodiumbisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodiumsulfite, sodium thiosulfate, thiourea and tocopherols.

As stated above, the compositions may optionally further comprise one orseveral adjuvant(s) or synergists(s). If adjuvant(s) or synergists(s)are used, non-limiting examples of those that can be used include citricacid, EDTA (ethylenediaminetetraacetate) and salts, hydroxyquinolinesulfate, phosphoric acid and tartaric acid.

As stated above, the compositions may optionally further comprise one orseveral preservative(s). If preservative(s) are used, non-limitingexamples of those that can be used include benzalkonium chloride,benzethonium chloride, benzoic acid and salts, benzyl alcohol, boricacid and salts, cetylpyridinium chloride, cetyltrimethyl ammoniumbromide, chlorobutanol, chlorocresol, chorhexidine gluconate orchlorhexidine acetate, cresol, ethanol, imidazolidinyl urea, metacresol,methylparaben, nitromersol, o-phenyl phenol, parabens, phenol,phenylmercuric acetate/nitrate, propylparaben, sodium benzoate, sorbicacids and salts, β-phenylethyl alcohol and thimerosal.

The pharmaceutical formulation can be administered to a subject in needof conscious sedation, procedural sedation, analgesia and/orpre-sedation, and in general to any kind of non-general anesthesia, byvarious local administrations. More specifically, the pharmaceuticalformulations described herein may be prescribed by ordinarily skilledmedical practitioners such as physicians, as the means of conscioussedation or pre-sedation. This is intended to be used by certainpatients who experience or expect to experience high anxiety, bouts ofpanic attacks, disquietude, apprehension, angst or similar feeling ofpsychological discomfort or distress prior to, or during, some medicalor surgical procedures described in more detail below. The patients maybe of any age, i.e., including children, adolescents and adults.

For example, the formulation can be used prior to various outpatientsurgeries and medical procedures, both invasive and non-invasive, suchas an ophthalmic surgery, outpatient medical or surgical procedures,dental procedures, of urological procedures, obstetric and gynecologicalprocedures, gastrointestinal procedures, otolaryngological procedures,cosmetic surgery procedures, dermatological procedures, podiatricprocedures, orthopedic procedures, emergency medical treatments,psychiatric treatments, and veterinarian procedures.

Specific representative examples of the procedures that are amenable tothe use of the formulation include, without limitation, cataractsurgery, glaucoma surgery, corneal surgery, eyelid surgery, retinalsurgery, tooth extraction, oral surgery, root canal surgery, medicalimaging procedures (e.g., MRI or CAT scanning, especially for patientssuffering from claustropbobia), biopsy, bone marrow harvesting,colonoscopy, endoscopy and laparoscopy.

In some non-limiting embodiments, various routes of local administrationmay be used. Non-limiting examples of acceptable local routes includerectal administration, nasal administration (including via a nasalspray), oral spray administration, transdermal administration, andtransmucosal administration including that utilizing a transmucosal gel.Those having ordinary skill in the art will prepare compositions thatare suitable for a particular route of local administration that isselected. The local administration may be used instead or intravenousadministration or to complement the latter, as appropriate.

It will be understood by those having ordinary skill in the art that thespecific dose level and frequency of dosage for any particular patientmay be varied and will depend upon many factors including the activityof the specific compound employed, the metabolic stability and length ofaction of that compound, the age, body weight, general health, gender,diet and the severity of the particular condition being treated.

According to further embodiments, methods for fabricating theabove-described pharmaceutical compositions are provided. A one-batchformulation method may be used, where the components of thepharmaceutical formulation can be combined in single container; thecomponents may be added to the container simultaneously orconsecutively. Alternatively, a two- or multiple-batch method(s) may beused if desired, where each component of the pharmaceutical formulationcan be combined in separate container followed by combining the contentsof each container.

In one exemplary, non-limiting procedure, pre-measured quantities ofeach ingredient in the form of dry powder can be mixed to form a dryblend followed by mixing it with a liquid or gel base as describedabove.

In additional embodiments, pharmaceutical kits are provided. The kitincludes a sealed container approved for the storage of solidpharmaceutical compositions, the container containing one of theabove-described pharmaceutical compositions an instruction for the useof the composition and the information about the composition are to beaffixed to the container or otherwise enclosed with it.

The following examples are provided to further elucidate the advantagesand features of the present invention, but are not intended to limit thescope of the invention. The examples are for the illustrative purposesonly. USP pharmaceutical grade products were used in preparing theformulations described below.

Example 1. Preparing a Pharmaceutical Composition in the Form of aTroche

A pharmaceutical composition may be prepared as described below. Thefollowing products can be used in the amounts and concentrationsspecified:

-   -   (a) about 0.2 g of midazolam;    -   (b) about 2.0 g of ketamine hydrochloride;    -   (c) about 0.2 g of propanolol ondansetron hydrochloride;    -   (d) about 1 mL of lemon oil flavoring; and    -   (e) about 15.5 g of standard troche base (comprising polyglycol        1450, polyglycol 400, gelatin, sodium saccharin and steviaside).

The troche base can be melted at low heat while being stirred; whencompletely molten, the heat can be turned off with continued stirring.All the dry ingredients, pre-weighed can be added into the molten basefollowed by adding the flavoring and well mixed together.

A half-moon shaped troche mold can be lightly sprayed with Pam (or asuitable oil/releasing agent) to cover the entire surface of the moldand the mixture prepared as explained above can then be poured into themold and allowed to cool and harden at room temperature. A heat gun canthen be used to smooth out the surface followed by another round ofcooling at room temperature followed by removing the so prepared trochefrom the mold, placing it into a prescription vial and labeling thevial. The troche is now ready to be administered.

Example 2. Preparing a Pharmaceutical Composition in the Form of aSuppository

A pharmaceutical composition may be prepared as described below. Thefollowing products can be used in the amounts and concentrationsspecified:

-   -   (a) about 0.3 g of midazolam;    -   (b) about 2.5 g of ketamine hydrochloride;    -   (c) about 0.249 g ondansetron hydrochloride dihydrate;    -   (d) about 2.0 g of silica gel; and    -   (e) about 235 g of standard suppository base, i.e., waxy        fatty-acid base comprising a blend of saturated polyglycolysed        glycerides.

The suppository base can me melted in a beaker at a temperature of about50° C. The rest of ingredients (i.e., midazolam, ketamine HCl,ondansetron hydrochloride dihydrate, and silica gel), pre-weighed, canbe added into the molten suppository base while being constantlystirred, followed by discontinuing the heat with continued mixing untila homogeneous suspension is obtained. Finally, using a syringe withrectal tip the warm suspension can be placed into 2.4 g suppositoryshells and allowed to cool, followed by heat sealing the suppositoryshells, labeling and packaging.

Example 3. Preparing a Pharmaceutical Composition in the Form of a NasalSpray

A pharmaceutical composition may be prepared as described below. Thefollowing products can be used in the amounts and concentrationsspecified:

-   -   (a) about 2.5 g of midazolam;    -   (b) about 10.5 g of ketamine hydrochloride;    -   (c) about 1.245 g ondansetron hydrochloride dihydrate;    -   (d) about 0.1 g of edetate disodium powder;    -   (e) about 1.0 g of 1% solution of benzalkonium chloride; and    -   (f) about 100.0 mL of purified water.

Midazolam, ketamine hydrochloride, and ondansetron hydrochloridedihydrate, pre-weighed, can be combined in an appropriate container andabout 70% of water can be added while being constantly stirred, followedby adding a quantity of hydrochloric acid sufficient to have midazolamand ondansetron completely dissolve. The solution of benzalkoniumchloride and edetate disodium powder can be then added and mixed in todissolve. The pH of the resulting solution can then be adjusted to bewithin about 2.8 to 3.2 range using a solution of hydrochloric acidand/or sodium hydroxide followed by packaging with metered nasal spraytip.

Example 4. Preparing a Pharmaceutical Composition for TransdermalAdministration

A pharmaceutical composition may be prepared as described below. Thefollowing products can be used in the amounts and concentrationsspecified:

-   -   (a) about 0.3 g of midazolam;    -   (b) about 2.5 g of ketamine hydrochloride;    -   (c) about 0.240 g ondansetron hydrochloride dihydrate;    -   (d) about 22.0 g of lecithin organogel liquid (available from,        e.g., Letco Medical, Decatur, Ala.); and    -   (e) about 100.0 g of 30% PLURONIC F-127® gel.

Midazolam, ketamine hydrochloride, and ondansetron hydrochloridedihydrate, pre-weighed, can be combined in an empty tared mixing jarfollowed by adding lecithin organogel and PLURONIC F-127 mixing using anautomatic mixer on speed 2 and filling a tube with the product andsealing it.

Example 5. Preparing a Pharmaceutical Composition for TransmucosalAdministration in the Form of a Mucoadhesive Gel

A pharmaceutical composition may be prepared as described below. Thefollowing products can be used in the amounts and concentrationsspecified:

-   -   (a) about 0.3 g of midazolam;    -   (b) about 2.5 g of ketamine hydrochloride;    -   (c) about 0.249 g ondansetron hydrochloride dihydrate;    -   (d) about 15.0 g of PLURONIC F-127®;    -   (e) about 4.0 g of sodium hyaluronate, cosmetic grade;    -   (f) about 3.0 g of CARBOMER 940® powder; and    -   (g) about 100.0 mL of purified water.

Midazolam, ketamine hydrochloride, and ondansetron hydrochloridedihydrate, pre-weighed, can be combined in an appropriate container andabout 50% of water can be added while being constantly stirred, followedby adding pre-weighed quantities of sodium hyaluronate and PLURONICF-127®, with continued mixing. Then a pre-weighed quantity of CARBOMER940® powder may be added, taking care that clumping would not occur, andthe use of high shear mixing may be needed to achieve complete hydrationof the gel. Then, mixing may continue until a clear gel is obtainedfollowed by adding the remainder of water, packaging and labeling.

Although the invention has been described with reference to the aboveexamples, it will be understood that modifications and variations areencompassed within the spirit and scope of the invention. Accordingly,the invention is limited only by the following claims.

What is claimed is:
 1. A method for inducing conscious sedation,procedural sedation, analgesia, pre-sedation or a non-general anesthesiain a patient in need thereof, comprising administering to the patient apharmaceutical composition comprising: (a) a therapeutically effectivequantity of a first pharmaceutically active compound selected from thegroup consisting of midazolam, diazepam, lorazepam, flunitrazepam,alprazolam, chlordiazepoxide, clonazepam and clorazepate, andpharmaceutically acceptable salts, hydrates, solvates or N-oxidesthereof; (b) a therapeutically effective quantity of a secondpharmaceutically active compound selected from the group consisting ofketamine, dextrorphan, etomidate, methadone, memantine, amantadine,dextromethorphan, and pharmaceutically acceptable salts, hydrates,solvates or N-oxides thereof; (c) a pharmaceutically suitable bindertherefor; and (d) optionally, a pharmaceutically acceptable excipient,wherein the pharmaceutical composition is administered by a methodselected from the group consisting of rectal administration, oral sprayadministration, transdermal administration, and transmucosaladministration, to induce conscious sedation, procedural sedation,analgesia, pre-sedation or non-general anesthesia thereby.
 2. The methodof claim 1, wherein the pharmaceutical composition further comprises atherapeutically effective quantity of a third pharmaceutically activecompound selected from the group consisting of β-blockers, antiemeticmedicaments, NSAIDs, antihistamines, α-2-adrenergic agonists, and painrelievers and combinations thereof, or pharmaceutically acceptablesalts, hydrates, solvates or N-oxides thereof.
 3. The method of claim 2,wherein the β-blocker, the α-2-adrenergic agonist or the pain relieveris selected from the group consisting of metoprolol, propranolol,acebutolol, nadolol, atenolol, betaxolol, esmolol, bisoprolol fumarate,carvedilol, nebivolol, penbutolol, timolol, sotalol, dexmedetomidinehydrochloride, and acetaminophen.
 4. The method of claim 2, wherein theantiemetic medicament is selected from the group consisting ofondansentron, dolasetron, granisetron, palonosetron, promethazine,imenhydrinate, and meclizine.
 5. The method of claim 2, wherein theNSAID is selected from the group consisting of bromfenac, ketorolac,etodolac, sulindac, diclofenac, aceclofenac, nepafenac, tolmetin,indomethacin, nabumetone, ketoprofen, dexketoprofen, ibuprofen,flurbiprofen, dexibuprofen, fenoprofen, loxoprofen, oxaprozin, naproxen,aspirin, salicylic acid, diflunisal, salsalate, mefenamic acid,meclofenamic acid, flufenamic acid, tolfenamic acid, meloxicam,piroxicam, ternoxicam, droxicam, lornoxicam, isoxicam, celecoxib,rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib,nimesulide, clonixin, and licofelone.
 6. The method of claim 2, whereinthe antihistamine is selected from the group consisting of hydroxyzinepamoate, hydroxyzine hydrochloride, diphenhydramine hydrochloride,meclizine, chlorpheniramine, clemastine, promethazine, andprochlorperazine.
 7. The method of claim 2, wherein the pharmaceuticalcomposition further comprises a therapeutically effective quantity of areceptor antagonist to benzodiazepines.
 8. The method of claim 7,wherein the receptor antagonist is flumazenil.
 9. The method of claim 2,wherein the first pharmaceutically active compound is midazolam, thesecond pharmaceutically active compound is ketamine and the thirdpharmaceutically active compound is metoprolol, at amidazolam:ketamine:metoprolol ratio of between about 1:2:1 and about1:10:1 by mass.
 10. The pharmaceutical composition of claim 2, whereinthe first pharmaceutically active compound is midazolam, the secondpharmaceutically active compound is ketamine and the thirdpharmaceutically active compound is ondansentron, at amidazolam:ketamine:ondansentron ratio of about 3:25:2 by mass.
 11. Themethod of claim 1, wherein the binder comprises a polyglycol selectedfrom the group consisting of polyethylene glycol, polyethylene oxide,methoxypolyethylene glycol, polypropylene glycol and polybutyleneglycol, or derivatives thereof.
 12. The method of claim 1, wherein theexcipient is present and comprises a member selected from the groupconsisting of gelatin, sodium saccharin, stevioside, peppermint oil,cherry flavor, lemon oil, raspberry flavor, any natural or artificialfruit, vegetable, flower, beverage or candy flavor, and combinationsthereof.
 13. The method of claim 1, wherein the binder comprises aproduct selected from the group consisting of methoxypolyethyleneglycol, polypropylene glycol, polybutylene glycol, PEG-laureates,PEG-dilaureates, PEG-oleates, PEG-dioleates, PEG-trioleates,PEG-stearates, PEG-distearates, castor oil derivatives of PEG, palmkernel oil derivatives of PEG, corn oil derivatives of PEG, soya oilderivatives of PEG, cholesterol derivatives of PEG, phytosterolderivatives of PEG, caprate/caprylate glycerides derivatives of PEG,tocopheryl succinate derivatives of PEG, octylphenol derivatives of PEG,nonylphenol derivatives of PEG, polyglyceryl-10-laurate,polyglyceryl-10-oleate, POE-lauryl ethers, POE-oleyl ethers, POE-stearylethers, polysorbates, monostearate, monolaurate and monopalmitatederivatives of sucrose, and products ofpoly(oxypropylene)-co-poly(propylene oxide) family.
 14. The method ofclaim 1, wherein the medical procedure is selected from the groupconsisting of an ophthalmic surgery, a dental procedure, an outpatientmedical procedure, obstetric and gynecological procedures, agastrointestinal procedure, an otolaryngological procedure, a cosmeticsurgery procedure, a dermatological procedure, a podiatric procedure, anorthopedic procedure, an emergency medical treatment, a psychiatrictreatment, a urological procedure, and a veterinarian procedure.
 15. Themethod of claim 14, wherein the ophthalmic surgery is selected from thegroup consisting of a cataract surgery, a glaucoma surgery, cornealsurgery, eyelid surgery, and retinal surgery.
 16. The method of claim14, wherein the dental procedure is selected from the group consistingof a tooth extraction, an oral surgery, and a root canal surgery. 17.The method of claim 14, wherein the outpatient surgical procedure isselected from the group consisting of a medical imaging procedure,biopsy, bone marrow harvesting, colonoscopy, endoscopy, and alaparoscopic procedure.
 18. The method of claim 1, wherein the patientexperiences or expects to experience high anxiety, bouts of panicattacks, disquietude, apprehension, or angst prior to, or during, themedical procedure.
 19. The method of claim 1, wherein the pharmaceuticalcomposition is administered by rectal administration.